PORTAL RADIOGRAPHY IN VETERINARY RADIATION ONCOLOGY: OPTIONS AND CONSIDERATIONS

Portal radiography involves the acquisition of images to visualize radiation treatment field(s) using the radiation treatment source. The standard has been the use of film-based systems with improvements over the years in film–screen technology providing near diagnostic quality images. More recent advances have included the development of digital systems with such notable improvements including ability to window/level images to enhance viewing and readability, and significant shortening of the time required to acquire images.     

INVITED REVIEW—IMAGE REGISTRATION IN VETERINARY RADIATION ONCOLOGY: INDICATIONS,IMPLICATIONS, AND FUTURE ADVANCES

The field of veterinary radiation therapy (RT) has gained substantial momentum in recent decades with significant advances in conformal treatment planning, image‐guided radiation therapy (IGRT), and intensity‐modulated (IMRT) techniques. At the root of these advancements lie improvements in tumor imaging, image alignment (registration), target volume delineation, and identification of critical structures. Image registration has been widely used to combine information from multimodality images such as computerized tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) to improve the accuracy of radiation delivery and reliably identify tumor‐bearing areas. Many different techniques have been applied in image registration. This review provides an overview of medical image registration in RT and its applications in veterinary oncology. A summary of the most commonly used approaches in human and veterinary medicine is presented along with their current use in IGRT and adaptive radiation therapy (ART). It is important to realize that registration does not guarantee that target volumes, such as the gross tumor volume (GTV), are correctly identified on the image being registered, as limitations unique to registration algorithms exist. Research involving novel registration frameworks for automatic segmentation of tumor volumes is ongoing and comparative oncology programs offer a unique opportunity to test the efficacy of proposed algorithms.     

INVITED REVIEW: STUDY DESIGN CONSIDERATIONS FOR CLINICAL RESEARCH IN VETERINARY RADIOLOGY AND RADIATION ONCOLOGY

High quality clinical research is essential for advancing knowledge in the areas of veterinary radiology and radiation oncology. Types of clinical research studies may include experimental studies, method‐comparison studies, and patient‐based studies. Experimental studies explore issues relative to pathophysiology, patient safety, and treatment efficacy. Method‐comparison studies evaluate agreement between techniques or between observers. Patient‐based studies investigate naturally acquired disease and focus on questions asked in clinical practice that relate to individuals or populations (e.g., risk, accuracy, or prognosis). Careful preplanning and study design are essential in order to achieve valid results. A key point to planning studies is ensuring that the design is tailored to the study objectives. Good design includes a comprehensive literature review, asking suitable questions, selecting the proper sample population, collecting the appropriate data, performing the correct statistical analyses, and drawing conclusions supported by the available evidence. Most study designs are classified by whether they are experimental or observational, longitudinal or cross‐sectional, and prospective or retrospective. Additional features (e.g., controlled, randomized, or blinded) may be described that address bias. Two related challenging aspects of study design are defining an important research question and selecting an appropriate sample population. The sample population should represent the target population as much as possible. Furthermore, when comparing groups, it is important that the groups are as alike to each other as possible except for the variables of interest. Medical images are well suited for clinical research because imaging signs are categorical or numerical variables that might be predictors or outcomes of diseases or treatments.     

A SURVEY OF VETERINARY RADIATION FACILITIES IN 2010

A survey of veterinary radiation therapy facilities in the United States, Canada, and Europe was done in 2010, using an online survey tool, to determine the type of equipment available, radiation protocols used, caseload, tumor types irradiated, as well as other details of the practice of veterinary radiation oncology. The results of this survey were compared to a similar survey performed in 2001. A total of 76 facilities were identified including 24 (32%) academic institutions and 52 (68%) private practice external beam radiation therapy facilities. The overall response rate was 51% (39/76 responded). Based on this survey, there is substantial variation among facilities in all aspects ranging from equipment and personnel to radiation protocols and caseloads. American College of Veterinary Radiology boarded radiation oncologists direct 90% of the radiation facilities, which was increased slightly compared to 2001. All facilities surveyed in 2010 had a linear accelerator. More facilities reported having electron capability (79%) compared to the 2001 survey. Eight facilities had a radiation oncology resident, and academic facilities were more likely to have residents. Patient caseload information was available from 28 sites (37% of radiation facilities), and based on the responses 1376 dogs and 352 cats were irradiated in 2010. The most frequently irradiated tumors were soft tissue sarcomas in dogs, and oral squamous cell carcinoma in cats.     

RADIATION AND CISPLATIN FOR TREATMENT OF CANINE URINARY BLADDER CARCINOMA

Two cases of canine urinary bladder carcinoma were treated with combined radiation and cisplatin. Total radiation dose was 4400 cGy for one dog and 4800 cCy for the other. Cobalt 60 radiation was fractioned using 400 cGy per fraction. Cisplatin was administered intraarterially at a dose of 50 mg/m² divided equally six to seven hours before the first three radiation fractions. Cisplatin was administered before the last three radiation fractions at the same dose and time, but was infused intravenously. Objective evaluation using double contrast cystograms revealed reduction in tumor size in both dogs. The therapy was well-tolerated with minimal side effects.     

A SURVEY OF VETERINARY RADIATION FACILITIES IN THE UNITED STATES DURING 2001

A survey of veterinary radiation therapy facilities in the United States was done in 2001 to determine the type of equipment available, radiation protocols used, case load, tumor types irradiated, as well as other details of the practice of radiation oncology. A total of 42 sites were identified and included 17 (40%) academic institutions, and 25 (60%) private practice external beam radiation facilities. The overall response rate was 79% (33/42 responded). Based on this survey there is substantial variation between facilities in all aspects ranging from equipment and personnel to radiation protocols and caseloads. American College of Veterinary Radiology boarded radiation oncologists direct 76% of the radiation facilities at academic institutions and 60% of the private practice facilities. Three facilities had orthovoltage radiation units only, and 30 facilities had mega-voltage equipment: cobalt 60 or linear accelerator. A total of 18 facilities had linear accelerators with three of these off site at a human radiation facility. Patient load information was available from 31 sites (74% of the radiation facilities in the United States), and based on the responses 2790 dogs and 1081 cats were irradiated in 2001. Canine mast cell tumors were the most frequently irradiated tumor. This represents the first survey of veterinary radiation facilities in the United States and provides information on the specialty of veterinary radiation oncology.     

RADIATION THERAPY COMMUNICATION—REIRRADIATION OF A NASAL TUMOR IN A BRACHYCEPHALIC DOG USING INTENSITY MODULATED RADIATION THERAPY

A 5‐year‐old spayed female Shih Tzu was referred for evaluation of a nasal transitional carcinoma. A total lifetime dose of 117 Gy was delivered to the intranasal mass in three courses over nearly 2 years using fractionated intensity modulated radiation therapy (IMRT) to spare normal tissues. Clinically significant late normal tissue side effects were limited to bilaterally diminished tear production. The patient died of metastatic disease progression 694 days after completion of radiation therapy course 1. This case demonstrates that retreatment with radiation therapy to high lifetime doses for recurrent local disease may be well tolerated with IMRT.     

USE OF PORTAL RADIOGRAPHY TO INCREASE ACCURACY OF DOSE DELIVERY IN RADIATION THERAPY

Port films were acquired for all radiation therapy patients (n = 132) treated over a thirteen month period to 1] assist in initial treatment field set-up on Day 1, 2] for quality assurance with a second port film taken on Day 7 of radiation therapy, and 3] as a means to document the radiation treatment field as a part of the patients permanent medical record. Port films were used for both patients treated with a definitive course of radiation (n = 97 patients), and those treated palliatively (n = 35 patients). The portal radiographs were valuable in terms of the initial set-up, and to correct for any positioning or other errors at the time of the one week recheck. Changes were made, based on the initial port film on Day 1, in 53% and 57% of treatment fields for palliative and definitive radiation patients, respectively. The changes made in both definitively and palliatively irradiated patients were usually in field position, an increase in field size to include all of the tumor, or a decrease in field size to spare normal tissue. Fewer changes were necessary based on the Day 7 recheck port films, but these day-7 rechecks are recommended for quality control. Based on the high frequency of changes introduced because of the initial port film findings, it is recommended that port films be incorporated on a routine basis in veterinary radiation therapy.     

UNEXPECTED TOXICITY FOLLOWING USE OF GEMCITABINE AS A RADIOSENSITIZER IN HEAD AND NECK CARCINOMAS: A VETERINARY RADIATION THERAPY ONCOLOGY GROUP PILOT STUDY

Gemcitabine (2',2'-difluorodeoxycytidine) was given intravenously twice weekly to 10 cats with oral squamous cell carcinoma and 15 dogs with nasal carcinoma undergoing radiotherapy as a radiosensitizing agent. The average total radiation dose was 50 Gy for dogs and 54 Gy for cats given Monday-Friday (planned dose of 54 and 57 Gy, respectively). Dogs received an average of five doses of gemcitabine beginning at 50 mg/m2, and cats received an average of five doses of gemcitabine beginning at 25 mg/m2. Twelve of 15 dogs and five of 10 cats required chemotherapy dose reduction or postponement because of hematologic or normal tissue toxicity. The results herein do not support the use of gemcitabine at the studied dose and schedule, as significant hematologic and local tissue toxicity was observed in the studied patients. Pharmacokinetic data are necessary to best define the efficacy and optimal dose and schedule of gemcitabine in combination with traditional radiotherapy.     

A REVIEW OF PORTAL SCREEN-FILM TECHNOLOGY AND FIVE RADIOLOGISTS' EVALUATIONS OF SOME EXISTING PRODUCTS

Portal radiographs, radiographs made to document the accuracy of radiotherapy treatment fields, are typically of poor image contrast. Recently, a new portal film and screened-cassette system was marketed, the Kodak EC-L system, with the claim of greatly improved image contrast. This new EC-L system was tested on a canine cadaver exposed to Cobalt-60 teletherapy gamma radiation, and image quality was compared to earlier marketed Kodak portal film products. The EC-L system was found to provide portal images of improved contrast/quality.     

POTENTIAL FOR INTENSITY-MODULATED RADIATION THERAPY TO PERMIT DOSE ESCALATION FOR CANINE NASAL CANCER

We evaluated the impact of inverse planned intensity-modulated radiation therapy (IMRT) on the dose-volume histograms (DVHs) and on the normal tissue complication probabilities (NTCPs) of brain and eyes in dogs with nasal tumors. Nine dogs with large, caudally located nasal tumors were planned using conventional techniques and inverse planned IMRT for a total prescribed dose of 52.5 Gy in 3.5 Gy fractions. The equivalent uniform dose for brain and eyes was calculated to estimate the normal tissue complication probability (NTCP) of these organs. The NTCP values as well as the DVHs were used to compare the treatment plans. The dose distribution in IMRT plans was more conformal than in conventional plans. The average dose delivered to one-third of the brain was 10 Gy lower with the IMRT plan compared with conventional planning. The mean partial brain volume receiving 43.6 Gy or more was reduced by 25.6% with IMRT. As a consequence, the NTCPs were also significantly lower in the IMRT plans. The mean NTCP of brain was two times lower and at least one eye could be saved in all patients planed with IMRT. Another possibility with IMRT is dose escalation in the target to improve tumor control while keeping the NTCPs at the same level as for conventional planning. Veterinary     

TOLERABILITY AND TUMOR RESPONSE OF A NOVEL LOW‐DOSE PALLIATIVE RADIATION THERAPY PROTOCOL IN DOGS WITH TRANSITIONAL CELL CARCINOMA OF THE BLADDER AND URETHRA

Previously reported radiation protocols for transitional cell carcinoma of the canine lower urinary tract have been ineffective or associated with increased side effects. Objectives of this retrospective, cross‐sectional study were to describe safety of and tumor responses for a novel palliative radiation protocol for transitional cell carcinoma in dogs. Included dogs had cytologically or histologically confirmed transitional cell carcinoma of the bladder or urethra, and were treated with 10 once‐daily fractions (Monday–Friday) of 2.7 Gy. Thirteen dogs were sampled, with six treated using radiation as first‐line (induction) therapy and seven treated using radiation as rescue therapy after failing previous chemotherapy. Within 6 weeks of radiation, 7.6% (1/13) dogs had a complete response, 53.8% (7/13) partial response, 38.5% (5/13) stable disease, and none had progressive disease. Three patients presenting with urethral obstruction had spontaneous micturition restored during the treatment protocol. A single patient with unilateral ureteral obstruction was patent at recheck examination. Median survival time from time of initial diagnosis was 179 days. Median survival time from start of radiation was 150 days. Acute radiation side effects occurred in 31% (4/13) patients and were classified as grade 1 or 2. No significant late side radiation side effects were reported. No variables examined were identified as prognostic factors. Findings indicated that the reported radiation protocol was safe in this sample of dogs with bladder and urethral transitional cell carcinoma. Future prospective studies are needed to determine utility of this treatment as a rescue therapy in patients with complete urinary tract obstruction.     

USE OF RADIATION AND A SLOW-RELEASE CISPLATIN FORMULATION FOR TREATMENT OF CANINE NASAL TUMORS

The purpose of this study was to evaluate the combined use of radiation and a slow-release cisplatin chemotherapy formulation for treatment of malignant nasal tumors in dogs. In this retrospective analysis, 51 dogs were evaluated with respect to treatment toxicity, tumor type, stage of disease, cribriform plate involvement, and overall survival. In general, treatment was well tolerated. Mean and median survival as assessed by the Kaplan-Meier product limit method was 570 and 474 days, respectively. No other factors, including tumor type, stage of disease, or cribriform plate invasion had a significant impact on survival. In conclusion, a combination of slow release cisplatin chemotherapy and radiation for the treatment of canine nasal tumors is well tolerated. Results of this analysis warrant further study to elucidate possible other beneficial radiation potentiating drugs and dosing schedules.     

COMPARISON OF ISODOSE DISTRIBUTIONS IN CANINE BRAIN IN HETEROGENEITY-CORRECTED VERSUS UNCORRECTED TREATMENT PLANS USING 6 MV PHOTONS

Magnetic resonance (MR) images may be useful for radiation planning due to greater contrast resolution. One disadvantage of MR images for radiation planning is the inability to incorporate electron density information into the dose calculation algorithm. To assess the magnitude of this problem, we evaluated radiation dose distribution in canine brain by comparing computed tomography (CT)-based radiotherapy plans with and without electron density correction. Computerized radiotherapy plans were generated for 13 dogs with brain tumors using 6 MV photons. A tissue-contouring program was used to outline the gross tumor volume (GTV) and the planning target volume (PTV) for each patient. Two treatment plans were generated for each dog. First, the plan was optimized without heterogeneity correction. Then the heterogeneity correction was implemented without changing any other plan parameters. Isodose distributions and dose volume histograms (DVHs) were used to compare the two plans. The D95 (dose delivered to 95% of the volume) within the PTV was calculated for each treatment plan and differences in the D95s were compared. The mean D95s without and with heterogeneity correction were 49.1 +/- 0.7 and 48.9 +/- 1.0Gy, respectively. The absolute mean percent dose difference without and with heterogeneity correction was 1.0 - 0.9% (-1.3-3.2%) and was not considered to be clinically significant. We found no clinically significant difference between CT-based radiotherapy plans without and with heterogeneity correction for brain tumors in small animals, which supports the use of MR-based treatment planning for radiotherapy of small animal brain tumors.     

REPEATABILITY OF A PLANNING TARGET VOLUME EXPANSION PROTOCOL FOR RADIATION THERAPY OF REGIONAL LYMPH NODES IN CANINE AND FELINE PATIENTS WITH HEAD TUMORS

For canine and feline patients with head tumors, simultaneous irradiation of the primary tumor and mandibular and retropharyngeal lymph nodes (LNs) is often indicated. The purpose of this study was to assess the repeatability of a planning target volume (PTV) expansion protocol for these LNs. Two CT image sets from 44 dogs and 37 cats that underwent radiation therapy for head tumors were compared to determine LN repositioning accuracy and precision; planning‐CT (for radiation therapy planning) and cone‐beam CT (at the time of actual treatment sessions). Eleven percent of dogs and 65% of cats received treatment to their LNs. In dogs, the mandibular LNs were positioned more caudally (P = 0.0002) and the right mandibular and right retropharyngeal LNs were positioned more to the left side of the patient (P = 0.00015 and P = 0.003, respectively). In cats, left mandibular LN was positioned higher (toward roof) than the planning‐CT (P = 0.028). In conclusion, when the patient immobilization devices and bony anatomy matching are used to align the primary head target and these LNs are treated simultaneously, an asymmetrical PTV expansion that ranges 4–9 mm (dogs) and 2–4 mm (cats), depending on the directions of couch movement, should be used to include the LNs within the PTV at least 95% of the time.     

COMBINATION OF RADIATION THERAPY AND FIROCOXIB FOR THE TREATMENT OF CANINE NASAL CARCINOMA

Carcinomas represent two‐thirds of canine nasosinal neoplasms. Although radiation therapy (RT) is the standard of care, the incidence of local recurrence following treatment is high. Cyclooxygenase‐isoform‐2 (COX‐2) is expressed in 71–95% of canine nasal carcinomas and has been implicated in tumor growth and angiogenesis. Accordingly, COX‐2 inhibition seems rational to improve outcome. Dogs with histologically confirmed, previously untreated nasal carcinomas were randomized to receive the combination of a selective COX‐2 inhibitor (firocoxib) and palliative RT (Group 1) or RT and placebo (Group 2). Patients were regularly monitored with blood tests, urinalysis, and computed tomography. Pet owners were asked to complete monthly a quality‐of‐life questionnaire. Twenty‐four dogs were prospectively enrolled. According to Adams modified system, there were five stage 1, five stage 2, three stage 3, and 11 stage 4 tumors. Two dogs had metastases to regional lymph nodes. Median progression‐free interval and overall survival were 228 and 335 days in Group 1 (n = 12) and 234 and 244 days in Group 2 (n = 12). These differences were not statistically significant. The involvement of regional lymph nodes was significantly associated with progression‐free interval and overall survival (P = 0.004). Quality of life was significantly improved in Group 1 (P = 0.008). In particular, a significant difference was observed for activity and appetite. Although not providing a significant enhancement of progression‐free interval and overall survival, firocoxib in combination with RT is safe and improved life quality in dogs with nasal carcinomas.     

EFFECTS OF LOW-LEVEL EXPOSURE TO IONIZING RADIATION: CURRENT CONCEPTS AND CONCERNS FOR VETERINARY WORKERS*

The issue of biological effects caused by low-level exposure to ionizing radiation (0.1Sv/yr or 10 rem) is a concern of veterinary radiologists, clinicians and radiotherapists. Cellular damge from ionizing radiation is mediated by injury to DNA, some of which can be repaired. The most important harmful effects attributed to low-level exposure are carcinogenesis and mutation. Ionizing radiation may also cause embryonic and fetal damage, life span shortening and cataractogenesis. The estimated excess risk of mortality for all human cancers is 0.8% (800 deaths per 100,000) per 0.10 Sv of acute exposure; at low dose-rates, risk is presumed to be less. Ionizing radiation increases the frequencey of spontaneous genic and chromosomal mutations in man and animals. Studies of atomic bomb survivors imply that at least 1 Sv would be needed to double the spontaneous mutation rate for acute exposure to low-LET radiation. However, the doubling dose for chronic, low-level exposure may be 4 Sv or more. The human embryo and fetus are sensitive to excessive doses of ionizing radiation, with mental retardation the main concern in the low dose range. Paradoxically, there is scientific evidence that in some instances, chronic low-level exposure to ionizing radiation causes a beneficial or hormonic effect. For veterinary workers, occupational exposures appear to be well below the maximum permissible dose limit and the risk or probability of harmful effects is low if stringent radiation safety practices are maintained.     

RADIATION INDUCED VERTEBRAL OSTEOSARCOMA FOLLOWING TREATMENT OF AN INTRADURAL EXTRAMEDULLARY SPINAL CORD TUMOR IN A DOG

A 2-year-old neutered female Rottweiler diagnosed with an intradural extramedullary spinal cord tumor at T12-T13 was successfully treated with cytoreductive surgery followed by Cobalt 60 teletherapy. The dog was euthanised 5-and-a-half years later following diagnosis of an osteosarcoma involving the L1 and L2 vertebrae. Evidence of the initial tumor was not present at necropsy. The vertebral neoplasm fulfilled all of the accepted criteria for a radiation induced tumor. It was concluded that adjunctive irradiation should be considered for treatment of intradural extramedullary tumors of young dogs when total surgical resection is not possible. Although tumor induction is a rare late effect of radiation therapy, the risk of this occurrence should be considered when irradiating young animals. Radiation induced tumors in dogs have been associated with coarse fractionation schemes, or when large intraoperative doses have been administered. A lower dose per fraction, e.g., 3 Gy/fraction or less, is advisable when irradiating young dogs or any dog in which the life expectancy is 3-5 or more years after irradiation.     

ACCURACY OF CT AND MRI FOR CONTOURING THE FELINE OPTIC APPARATUS FOR RADIATION THERAPY PLANNING

Consistency and accuracy in normal tissue contouring in radiotherapy planning is important for comparison of dosimetry and toxicity data between studies. The purpose of this study was to determine whether magnetic resonance imaging (MRI) improves the accuracy of optic apparatus contouring as compared with computed tomography (CT) in both normal and acromegalic cats, and to construct a reference contour of the feline optic apparatus. Both CT and MRI were performed on cadavers of four healthy cats, as well as on five radiotherapy patients with feline acromegaly. Contours of the optic apparatus were drawn for each imaging study. The volume, center of mass, and the degree of concordance and mismatch were determined for each, and compared with a reference standard. Precontrast CT was found to overestimate volume as compared with MRI in acromegalic cats; no other statistically significant differences were identified in the volume, concordance index or mismatch index values of normal or acromegalic cats. Contours derived from T2‐wieghted MRI were subjectively considered to best match the reference standard. The caudal margin of the optic chiasm and the optic tracts were difficult to confidently contour regardless of which imaging modality and/or sequence was used. In conclusion, findings from the current study supported the use of a combination of CT and MR images and a priori knowledge of the shape of the optic apparatus to guide accurate contouring, especially where image contrast is not sufficient to clearly delineate the margins. Guidelines for feline optic apparatus contouring developed in this study can be used for future studies.     

RADIOBIOLOGICAL AND TREATMENT PLANNING STUDY OF A SIMULTANEOUSLY INTEGRATED BOOST FOR CANINE NASAL TUMORS USING HELICAL TOMOTHERAPY

Feasibility of delivering a simultaneously integrated boost to canine nasal tumors using helical tomotherapy to improve tumor control probability (TCP) via an increase in total biological equivalent uniform dose (EUD) was evaluated. Eight dogs with varying size nasal tumors (5.8-110.9 cc) were replanned to 42 Gy to the nasal cavity and integrated dose boosts to gross disease of 45.2, 48.3, and 51.3 Gy in 10 fractions. EUD values were calculated for tumors and mean normalized total doses (NTD(mean)) for organs at risk (OAR). Normal Tissue Complication Probability (NTCP) values were obtained for OARs, and estimated TCP values were computed using a logistic dose-response model and based on deliverable EUD boost doses. Significant increases in estimated TCP to 54%, 74%, and 86% can be achieved with 10%, 23%, and 37% mean relative EUD boosts to the gross disease, respectively. NTCP values for blindness of either eye and for brain necrosis were < 0.01% for all boosts. Values for cataract development were 31%, 42%, and 46% for studied boost schemas, respectively. Average NTD(mean) to eyes and brain for mean EUD boosts were 10.2, 11.3, and 12.1 Gy3, and 7.5, 7.2, and 7.9 Gy2, respectively. Using helical tomotherapy, simultaneously integrated dose boosts can be delivered to increase the estimated TCP at 1-year without significantly increasing the NTD(mean) to eyes and brain. Delivery of these treatments in a prospective trial may allow quantification of a dose-response relationship in canine nasal tumors.